Chlorhexidine (N,N′″1,6-Hexanediylbis[N′-(4-chlorophenyl)(imidodicarbonimidic diamide)] or (1E)-2-[6-[[amino-[(E)-[amino-(4-chloroanilino)methylidene]amino]methylidene]amino]hexyl]-1-[amino-(4-chloroanilino)methylidene]guanidine) is a bis-biguanide antiseptic and disinfectant that has bactericidal and bacteriostatic action against a wide range of gram-positive and gram-negative bacteria. Chlorhexidine has been used as a topical, antimicrobial tooth coating for the reduction of tooth decay in permanent teeth. U.S. Pat. No. 4,496,322 describes a dental varnish containing an antimicrobial agent, specifically chlorhexidine diacetate/acetate, a benzoin gum, and an orally-acceptable solvent that, when applied to teeth, dries to a film, that provides sustained release of the antimicrobial agent. An improvement on this technology was described in U.S. Pat. No. 4,883,534 that further provided a sealing composition, applied to the varnish, to extend the length of the antimicrobial protection provided by the varnish.
Chlorhexidine is also used in disinfectants (disinfection of the skin and hands), cosmetics (additive to creams, toothpaste, deodorants, and antiperspirants), and pharmaceutical products (preservative in eye drops, active substance in wound dressings and antiseptic mouthwashes). CN 1231929 has described chlorhexidine diacetate based compositions for use as a deodorizing agent in hosiery and socks. CN 1090904 described the incorporation of chlorhexidine in the preparation of hygiene supplies. US 2011/0146680 has described incorporating chlorhexidine gluconate into silicone catheters.
Benefits related to the addition of chlorhexidine in oral hygiene compositions have been widely reported in various studies. Loe and Harald, eds., In; Supplement No. 16, Vol. 21, 1986 to the Journal of Periodontal Research, presented articles entitled “Chlorhexidine in the Prevention and Treatment of Gingivitis.” This Supplement is representative of numerous published reports concerning the inclusion of chlorhexidine in oral hygiene compositions such as dentifrices and rinses. Oral care formulations containing chlorhexidine have also been documented in various patents. For example, U.S. Pat. No. 4,569,837, entitled “Pharmaceutical Preparation for Remedy of Periodontal Disease and Process for Production Thereof,” describes films for insertion in the gingival sulcus which contain and release chlorhexidine gluconate.
Efforts to treat periodontal/peri-implant disease have been impeded by several factors. Because the site of the bacterial infections is largely inaccessible to antimicrobial agents used in the oral cavity they are generally ineffective. Administration of antibiotics using controlled delivery devices has been shown to be a useful method of controlling the subgingival flora. However discontinuation of therapy is often associated with the return of the potential pathogens to the pockets. Long-term systemic and local antibacterial therapy has been used, but the potential dangers associated with this form of treatment, which include the development of resistant strains and super-imposed infections, do not warrant its serious consideration. Antibacterial agents such as chlorhexidine and quaternary ammonium salts in the form of mouth rinses have proved to be successful in preventing periodontal diseases. These agents, however, are unable to affect the subgingival flora when administered in this form as they do not penetrate into the pockets produced as a result of periodontitis and peri-implantitis. Hence, they cannot be used in mouth rinses to treat an established periodontal/peri-implant disease. By reacting the chlorhexidine base with acids, a large number of salts that are also sparingly water-soluble can be obtained.
It is important to note that the chlorhexidine products described to date have an immediate or burst release of the drug. There is therefore a need for sustained release formulations of chlorhexidine which enable a controlled delivery of the active substance where a longer term administration would be advantageous.
The present invention provides new crystal forms of salts of chlorhexidine as well as particles comprising such salts whereby the release mechanism can be switched between immediate release and controlled or sustained release. This is achievable by change in pH due to infection or by using external energy such as light, ultrasound or magnetic fields.